Prostate cancer (PCa) bone metastases are generally categorized as osteoblastic, based on radiographic imaging. However, on a cellular level, most patients have components of both bone resorption (osteoclastogenesis) and bone formation (osteoblastogenesis). Recently, we uncovered a PDGF D-initiated, novel protease/growth factor signaling network, critical for intraosseous PCa growth. Secreted as a latent homodimer, PDGF D contains a N-terminal CUB domain and a C-terminal growth factor domain (GFD). The proteolytic removal of the CUB domain is required for the growth factor domain dimer (PDGF D GFD-D) to activate its cognate receptor, ?-PDGFR. We demonstrated that the serine protease matriptase processes latent PDGF D into its active form in a 2-step manner. This involves the generation of a hemidimer (PDGF D HD), an intermediate form consisting of one full-length PDGF D chain and a single GFD subunit. Our preliminary studies have led us to hypothesize that PCa-derived PDGF D is capable of preparing a metastatic niche within the bone by inducing osteoclast activation via PDGF D HD-specific signaling (Aim 1), and by promoting human mesenchymal stem cell (hMSC) differentiation into osteoblasts through both PDGF D HD and GFD-D signaling (Aim 2). With regard to osteoblastogenesis, we further postulate that PDGF D HD activates the TGF?R/BMPR/SMAD signaling cascade, while PDGF D GFD-D preferentially activates the classic ?-PDGFR/Akt/p38 signaling in hMSCs. We further hypothesize that PDGF D-initiated bone remodeling is critical for intraosseous PCa growth, and thus PDGF D and its proteolytic activator matriptase are potential therapeutic targets (Aim 3). Completion of the proposed study will uncover novel functions of PDGF D in bone remodeling critical for PCa bone metastasis and provide valuable information for the development of PDGF inhibitors based on PDGF ligand-specific biology.